Compounds and methods for reducing prion expression

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PRNP RNA in a cell or animal, and in certain instances reducing the amount of PrP protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks spongiform changes in the brain, development of abnormal protein aggregates, neuronal loss, markers of neuronal loss, rapidly progressing dementia, and death. Such neurodegenerative diseases include prion diseases, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), familial Creutzfeldt-Jakob Disease (fCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru, Alzheimer's disease, or Parkinson's disease.

1 .- 87 . (canceled) 
     
     
         88 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         89 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         90 .- 97 . (canceled) 
     
     
         98 . The modified oligonucleotide of  claim 88  which is the sodium salt or the potassium salt. 
     
     
         99 . (canceled) 
     
     
         100 . A compound comprising a modified oligonucleotide according to the following chemical notation: Ges Teo  m Ceo Aeo Teo Aeo Ads Tds Tds Tds Tds  m Cds Tds Tds Ads Gds  m Ceo Tes Aes  m Ce (SEQ ID NO: 2809), wherein,
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE modified sugar,   d=a 2′-β-D deoxyribosyl sugar,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         101 .- 111 . (canceled) 
     
     
         112 . A population of modified oligonucleotides of  claim 88 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         113 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 112  and a pharmaceutically acceptable carrier or diluent. 
     
     
         114 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 88 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         115 . The pharmaceutical composition of  claim 114 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         116 . The pharmaceutical composition of  claim 115 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         117 . The pharmaceutical composition of  claim 115 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline. 
     
     
         118 . A population of modified oligonucleotides of  claim 89 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         119 . A population of modified oligonucleotides of  claim 98 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         120 . A population of compounds of  claim 100 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         121 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 89 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         122 . The pharmaceutical composition of  claim 121 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         123 . The pharmaceutical composition of  claim 122 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         124 . The pharmaceutical composition of  claim 122 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline. 
     
     
         125 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 98 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         126 . The pharmaceutical composition of  claim 125 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         127 . The pharmaceutical composition of  claim 126 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         128 . The pharmaceutical composition of  claim 126 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline. 
     
     
         129 . A pharmaceutical composition comprising the compound of  claim 100 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         130 . The pharmaceutical composition of  claim 129 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         131 . The pharmaceutical composition of  claim 130 , wherein the pharmaceutical composition consists essentially of the compound and artificial cerebrospinal fluid. 
     
     
         132 . The pharmaceutical composition of  claim 130 , wherein the pharmaceutical composition consists essentially of the compound and phosphate-buffered saline. 
     
     
         133 . The pharmaceutical composition of  claim 113 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         134 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 118 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         135 . The pharmaceutical composition of  claim 134 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         136 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 119 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         137 . The pharmaceutical composition of  claim 136 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid. 
     
     
         138 . A pharmaceutical composition comprising the population of compounds of  claim 120 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         139 . The pharmaceutical composition of claim  139 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid.